The present invention is related to sustained release of locally active agents and/or diagnostic agents from prosthetic implants into joint spaces or into other body spaces. In particular embodiments, the invention provides structures and compositions for the administration of local anesthetics in the joint areas in patients in need thereof.
Treatment of joint pain and infection after implantation of a joint prosthesis has hereto been based on the use of systemic treatment with antibodies and steroidal and nonsteroidal anti-inflammatory agents and analgesics as well as localized injection of steroidal anti-inflammatories, e.g., intra articular injection, and local anesthetics, either intra articular or proximal in the innervation of the painful joint. Localized treatment is generally preferred over systemic treatment, particularly when treating severe, localized joint pain, in order to avoid the untoward systemic effects associated with the high levels of both steroidal and nonsteroidal anti-inflammatory agents otherwise required. Local anesthetics alone have previously been injected into joint spaces to relieve pain, with mixed results.
Local anesthetics act by producing a loss of sensation in the localized area of administration in the body. The mechanism by which local anesthetics induce their effect, while not having been determined definitively, is generally thought to be based upon the ability to interfere with the initiation and transmission of the nerve impulse. The duration of action of a local anesthetic is proportional to the time during which it is in actual contact with the nervous tissues. Consequently, devices for formulations that maintain localization of the drug at the nerve greatly prolong anesthesia.
Local anesthetics are potentially toxic, yet must remain at the site long enough to allow sufficient time for the localized pain to subside. Therefore, it is of great importance that factors such as the choice of drug, concentration of drug, and rate and site of administration of drug be taken into consideration when contemplating their use.
Different devices and formulations are known in the art for administration of local anesthetics. For example, local anesthetics can be delivered in solution or suspension by means of injection, infusion, infiltration, irrigation, topically and the like. Injection or infusion can be carried out acutely, or if prolonged local effects are desired, localized anesthetic agents can be administered continuously by means of a gravity drip or infusion pump. Thus, local anesthetics such as bupivacaine have been administered by continuous infusion, e.g., for prolonged epidural or intrathecal administration.
Sustained release carriers for local anesthetics have been described. For example, U.S. Pat. Nos. 4,725,442 and 4,622,219 (Haynes) relate to methoxyflurane-containing microdroplets coated with a phospholipid prepared by sonication, which are suitable for intradermal or intravenous injection into a patient for inducing local anesthesia. Such microdroplets are said to cause long-term local anesthesia when injected intradermally, giving a duration of anesthesia considerably longer than the longest acting conventional local anesthetic (bupivacaine).
U.S. Pat. No. 5,188,837 (Domb) relates to a microsuspension system containing lipospheres having a layer of a phospholipid imbedded on their surface. The core of the liposphere is a solid substance to be delivered, or the substance to be delivered is dispersed in an inert vehicle. The substance to be delivered can be, e.g., nonsteroidal anti-inflammatory compounds, local anesthetics, water insoluble chemotherapeutic agents and steroids.
Other formulations directed to injectable microcapsules, etc. are known. For example, U.S. Pat. No. 5,061,492 describes prolonged release microcapsules of a water soluble drug in a bioabsorbable/resorbable polymer matrix which is composed of a copolymer of glycolic acid and a lactic acid. The microcapsules are prepared as an injectable preparation in a pharmaceutically acceptable vehicle. The particles of water soluble drug are retained in a drug-retaining substance dispersed in a matrix of the lactic/glycolic acid copolymer in a ratio of 100/1 to 50/50 and an average molecular weight of 5,000-200,000. The injectable preparation is made by preparing a water-in-oil emulsion of an aqueous layer of drug and drug retaining substance and an oil layer of the polymer, thickening and then water-drying.
U.S. Pat. No. 4,938,763 (Dunn et al.) is related to a bioabsorbable/resorbable polymer for use in providing syringeable, in-situ forming, solid bioabsorbable/resorbable implants for animals. In one aspect of this reference, a thermosetting system is utilized which utilizes copolymers which may be derived from polylactides and/or polyglycolides, combinations and mixtures of these and other polymers.
U.S. Pat. No. 4,293,539 (Ludwig et al.) relates to controlled release formulations comprised of a microbial agent dispersed throughout a copolymer derived from lactic acid and glycolic acid. The copolymer is derived from 60-95% lactic acid and 40-5% glycolic acid by weight, and has a molecular weight of 6,000-35,000. An effective amount of the copolymeric formulation is administered by subcutaneous or intramuscular administration.
WO 94/05265 describes improved bioabsorbable/resorbable sustained release systems consisting of a polymeric matrix incorporating a local anesthetic for the prolonged administration of the local anesthetic agent. The devices are selected on the basis of their degradation profiles; release of the topical anesthetic in a controlled manner over the period of preferably two weeks and degradation of the polymer in vivo with a half-life of less than six months, more preferably two months, to avoid localized inflammation. The disclosure states that an anti-inflammatory can be incorporated into the polymer with the local anesthetic to reduce encapsulation for optimal access of drug to its site of action. The anti-inflammatories that are said to be useful include steroids such as dexamethasone, cortisone, prednisone, and others routinely administered orally or by injection.
A relatively long-acting anesthetic, bupivacaine hydrochloride, is commercially available as Marcaine® Hydrochloride in sterile isotonic solutions with and without epinephrine (as bitartrate) 1:200,000 for injection via local infiltration, peripheral nerve block, and caudal and lumbar epidural blocks. After injection of Marcaine for caudal, epidural or peripheral nerve block in man, peak levels of bupivacine in the blood are reached in 30 to 45 minutes, followed by a decline to insignificant levels during the next three to six hours.
In addition, polymer microspheres have long been used for both medical and non-medical applications where sustained release of an agent of interest is desired. Nevertheless, prior to the present invention, the need for an effective method and formulation for delivering pain relief and other pharmaceutical or diagnostic treatments to the joints space has remained unmet. Further, the need for an effective method and formulation for delivering pain relief and other pharmaceutical or diagnostic treatments to body spaces adjacent areas where medical devices have been implanted has remained unmet until the present invention.